This invention relates to partially acetalized polyvinyl alcohol embolization particles or compositions (also known as “sponge” or foam particles) and to injectable compositions that may be introduced into or injected into the body perhaps via a catheter to form occlusive masses in a selected body region. One variation of the material is a particle composition in which the particles have physical parameters that, when those particles are produced or selected to complement the liquid medium used to carry the particles into the body, do not plug or tend not to plug the devices used to introduce the materials into the body. The desirable homogeneity of the suspension or composition provides two key functions. First, it imparts a non-clogging property since the particles are not allowed to aggregate. A second, subtler result is the evenness of the delivery of the particles through the catheter. Since the particles do not collect into a bolus before delivery, the physician is able more accurately to control the time and quantity of delivery. Although this may seem to be a coupled property, it is not. For example, purely spherical smooth surface particles that are not homogeneously suspended could be delivered without clogging. However, they would be injected en masse without fine control. This is an important distinction.
One example of the particle-liquid medium composition entails a composition in which the particles are substantially suspended in the liquid medium for a period of time suitable for passage of the particle-liquid medium through the step of introducing the combination to a chosen site in the body without substantial plugging or agglomeration in the delivery apparatus.
In use, the compositions may be introduced into the human body to block blood flow to portions of malfunctioning human organs such as the kidney, spleen, and liver or to block blood flow into the malfunctioning regions of blood vessels such as arterio-venous malformations (AVM) and aneurysms. Certainly the compositions may be used to occlude vessels providing blood both to malignant and to benign tumors. This type of treatment is often employed for uterine fibroids, benign uterine smooth muscle tumors.
“Embolization” is the generic term for the artificial blocking of blood flow. Embolization of a vessel to an organ or in an organ may be used for a number of reasons. Vessel embolization may be used, for instance, for: 1) control of bleeding caused by trauma, 2) prevention of profuse blood loss during an operation requiring dissection of blood vessels, 3) obliteration of a portion of or of a whole organ having a tumor, or 4) blocking of blood flow into abnormal blood vessel structures such as AVM's and aneurysms.
There are a variety of materials and devices which have been used for embolization. These include platinum and stainless steel microcoils, and polyvinyl alcohol sponges (Ivalon). See, Interventional Radiology, Dandlinger et al, ed., Thieme, N.Y., 1990:295-313. Liquid embolic agents come in a variety of forms, e.g., cyanoacrylate glues (n-butyl and iso-butyl cyanoacrylate glue); solutions of partially hydrolyzed polyvinylacetate; cellulose diacetate polymers in biocompatible solvents such as dimethylsulfoxide, analogues and homologues of dimethylsulfoxide, and ethanol; and cellulose acetates, ethylene vinyl alcohol copolymers, hydrogels, polyacrylonitrile, polyvinylacetate, cellulose acetate butyrate, nitrocellulose, copolymers of urethane/carbonate, copolymers of styrene/maleic acid in biocompatible solvents such as dimethylsulfoxide, ethanol and acetone.
Of these, the cyanoacrylate glues may have an advantage in ease of delivery in that they are liquid embolics. However, the constituent cyanoacrylate polymers have the disadvantage of being biodegradable. The degradation product, formaldehyde, is highly toxic to the neighboring tissues. See, Vinters et al, “The Histotoxocity of Cyanoacrylate: A Selective Review”, Neuroradiology 1985; 27:279-291. Another disadvantage of cyanoacrylate materials is that the polymer may adhere both to the blood vessel and to the tip of the catheter. Thus, physicians must retract the catheter immediately after injection of the cyanoacrylate embolic material or risk adhesion of the cyanoacrylate and the catheter to the vessel.
The other liquid embolic materials listed just above are precipitative materials. See, Sugawara et al, “Experimental Investigations Concerning a New Liquid Embolization Method: Combined Administration of Ethanol-Estrogen and Polyvinyl Acetate”, Neuro Med Chir (Tokyo) 1993; 33:71-76; Taki et al, “A New Liquid Material for Embolization of Arterio-Venous Malformations”, AJNR 1990:11:163-168; Mandai et al, “Direct Thrombosis of Aneurysms with Cellulose Acetate Polymer. Part I: Results of Thrombosis in Experimental Aneurysms.” J Neurosurgery 1992; 77:493-500. These materials employ a different mechanism in forming synthetic emboli than do the cyanoacrylate glues. Cyanoacrylate glues are monomeric and rapidly polymerize upon contact with blood. Precipitative materials, on the other hand, are pre-polymerized chains in which the polymer is dissolved in a solvent that is miscible with blood, but precipitate into an aggregate upon contact with that blood.
The first such precipitative material used in this way was polyvinyl acetate (PVAc). Takahashi et al. dissolved the polymer in an ethanol/water mixture and delivered the mixture to an AVM for embolization. Also, poly(ethylene-co-vinyl alcohol) (“EVAL”) and cellulose acetate (CA) dissolved in 100% DMSO have also been used in clinical procedures. See, Taki et al, “A New Liquid Material for Embolization of Arterovenous Malformations”, AJNR 1990; 11:163-168 and Mandai et al, “Direct Thrombosis of Aneurysms with Cellulose Polymer: Part I: Results of Thrombosis in Experimental Aneurysms”, J Neurosurgery 1992; 77:493-500. Partially hydrolyzed polyvinyl acetate in ethanol is also used, particularly for treatment of hepatic tumors. See, U.S. Pat. No. 6,160,025 (Slaikeau et al) and U.S. Pat. No. 5,925,683 (Park et al).
One potential problem in use of the precipitating polymers mentioned above is due to the use of organic solvents to dissolve the polymers, i.e., ethanol for PVAc and DMSO for EVAL and CA. These materials are strong organic solvents that can dissolve the catheter hub, and, in the case of DMSO, can damage microcapillary vessels and surrounding tissues. These solvents are also known to cause vasospasm of blood vessels. Although PVAc is soluble in solvents which are milder than those needed for dissolution of EVAL or CA, a PVAc solution has a problem of its own: its radio-opacity is very low, i.e., the contrast concentration is only 100 mg I/ml equivalent.
Polyvinyl alcohol particles have been used to embolize various sites for a number of years. See, Barr et al, “Polyvinyl Alcohol Foam Particle Sizes and Concentrations Injectable through Microcatheters”, JVIR 1998; 9:113-115 However, since these embolics are sponge-like and compressible, there is a potential for clogging in the catheters used for delivering the particles to the selected site in the body. See, Darden et al, “Polyvinyl Alcohol Particle Size and Suspension Characteristics”, American Journal of Neuroradiology June 1995; 16:1335-1343. These particles have even been mounted on wires to achieve delivery without clumping. See, Irie, U.S. Pat. No. 5,895,411. Others have added dispersants to the particles. See, Lee et al, U.S. Pat. No. 6,191,193
None of the cited references suggest the tailoring of physical and chemical characteristics of PVA particles to complement the density of the liquid medium used to carry the particles into the body and thereby form a highly dispersed composition of partially acetalized PVA particles in that liquid medium. Those references do not show a composition in which the particles tend not to clump nor to aggregate in the delivery equipment during an embolization procedure.